Investigation of serum tnf - alpha and il - 6 concentrations in patients with long - term hemodialysis

Nội dung text: Investigation of serum tnf - alpha and il - 6 concentrations in patients with long - term hemodialysis

1. Journal of military pharmaco-medicine n o2-2018 INVESTIGATION OF SERUM TNF-ALPHA AND IL-6 CONCENTRATIONS IN PATIENTS WITH LONG-TERM HEMODIALYSIS Nguyen Duc Loc*; Ha Hoang Kiem**; Vu Xuan Nghia*** SUMMRAY Objectives: To investigate serum TNF-α and IL-6 concentration in long-term hemodialysis patients (LHD) and find out the association between serum TNF-α and IL-6 concentration and some characteristics of LHD patients. Subjects and methods: A prospective, cross-sectional study in 107 LHD patients who treated at Hemodialysis Department, An Sinh Hospital from 2 - 2014 to 2 - 2017 and a control group of 51 healthy people. Urinary NGAL concentration had been measured in all 116 patients and healthy people. Results: TNF-α and IL-6 concentrations in study group were significantly higher than those in the control group with p < 0.001. 33.6% of patients had an increase in both TNF-α and IL-6 concentrations. This proportion was 31.8% for single increase in TNF-α and 10.3% for single increase in IL-6 concentration. IL-6 concentration had a positive correlation with hemodialysis duration (r = 0.46; p < 0.001). Mean value of TNF-α concentration in patients with hepatitis virus infection was significantly higher than those without infection with p < 0.05, while IL-6 concentration was significantly higher in preserved urine output patients compared with non-preserved urine output patients (p < 0.001). Elevated proportion of IL-6 concentration was significant higher in decreased albumin group compared with no change group (62.5% versus 38.6%) with p < 0.05. Conclusion: TNF-α and IL-6 concentrations were elevated in LHD patients. TNF-α, and IL-6 concentrations had strong relation with hemodialysis duration, hepatitis virus infection, preserved urine output and decreased albumin status in those patients. * Keywords: Long-term hemodialysis; TNF-α; IL-6. INTRODUCTION expression of cell surface receptors. These abnormalities are caused by impaired Chronic inflammation is one of the excretory function of kidney and the characteristics of LHD patients, which has accumulation of uremic toxins in addition been shown to be a strong predictor of to bioincompatibility of dialyzer membranes. morbidity and mortality in this population. The increased levels of specific cytokines Patients with chronic renal failure commonly such as Interleukin 6 (IL-6) and tumor present with abnormalities of immune necrosis factor alpha (TNF-α) or acute phase function strictly correlated with abnormalities proteins (C-reactive protein) have been of immune cell reactivity, phenotype found to be associated with cardiovascular alterations of receptors and altered disease (CVD) in LHD patients. * An Sinh Hospital ** 103 Military Hospital *** Military Medical University Corresponding author: Nguyen Duc Loc (ducloc09@yahoo.com) Date received: 02/12/2017 Date accepted: 23/01/2018 105
2. Journal of military pharmaco-medicine n o2-2018 IL-6 and high-sensitivity C-reactive * Inclusion criteria: protein (hs-CRP) are two inflammatory - Patients with LHD. markers or mediators which are prone to - Hemodialysis duration ≥ 3 months. an increased serum level in end-stage - Causes of chronic renal failure renal disease (ESRD), infections, include: chronic glomerulonephritis, chronic cerebrovascular accidents, myocardial pyelonephritis, hypertension and diabetes. infarction, malignancies, and rheumatic - Patient's age ≥ 18. diseases. TNF-α is a pro-inflammatory cytokine, but mediates both other pro- - Patients are being filtered with low inflammatory and anti-inflammatory ultrafiltration coefficient. cytokines. TNF-α has regulatory effect on - Agree to participate in research. plasminogen activator inhibitor (PAI-1) * Exclusion criteria: expression and secretion by vessel - Severe heart or liver failure. endothelial cells, the main fibrinolysis - End-stage cancer. inhibitor elevated level of TNF-α associated with an increased risk for vascular - Having acute diseases such as: diseases. TNF-α in a variety of diseases bacterial infections, myocardial infarction, has been reported, and TNF-α causes acute heart failure, cerebral stroke. hypertrophy as well as negative inotropic - Difficulties in the implementation of effects on cardiac myocytes. Circulating intravascular pathway. TNF-α concentrations is reported elevated - Patients with conditions requiring in end-stage renal disease patients special filtration such as acute pulmonary undergoing LHD. Therefore, according to edema, hyperkalemia. the important roles of above factors, we - Having surgery within 1 month. conducted this research for the aim: 2. Methods. - Investigate serum TNF-α and IL-6 * Study design: A prospective, cross- concentration in patients with chronic sectional descriptive study. kidney disease undergoing LHD. * Steps of study: - Find out the association of serum - Ask for medical history and some TNF-α and IL-6 concentration with some main clinical symptoms. clinical characteristics of LHD patients: hemodialysis duration, oliguric state, albumin - Clinical examination and routine concentration, and hepatitis virus infection. laboratory tests. - Have some basic treatment. SUBJECTS AND METHODS - LHD using 2 different methods. 1. Subjects. - Quantification of serum TNF-α and The study was conducted with a group IL-6 levels (before and after intervention). of 107 LHD patients at Hemodialysis - Collect and process data according to Department, An Sinh Hospital from 2 - statistical algorithm. 2014 to 2 - 2017 and a control group of * Statistical analysis: Using SPSS 17 31 healthy people. for window and Epical 2,000 software. 106
3. Journal of military pharmaco-medicine n o2-2018 RESULTS AND DISCUSSIONS 1. Serum TNF-α and IL-6 concentration in study group. Table 1: Comparing serum TNF-α and IL-6 concentration between study group and control group. Characteristics Study group (n = 107) Control group (n = 31) p Mean ± SD 772.3 ± 280.3 365.0 ± 142.2 < 0.001 TNF-α Min 299.6 185.8 (ng/L) Max 2,113.6 703.4 Mean 11.8 ± 5.7 6.7 ± 1.7 < 0.001 IL-6 Min 6.3 2.9 (ng/L) Max 35.3 11.0 TNF-α and IL-6 levels in study group were significantly higher than in the control group with p < 0.001. Table 2: Changes of TNF-α and IL-6 levels in study group (n = 107). Characteristics n % Increased 70 65.4 TNF-α (ng/L) No change 37 34.6 Increased 47 43.9 IL-6 (ng/L) No change 60 56.1 - The percentage of patients with increased TNF-α and IL-6 concentration were 65.4% and 43.9%, respectively. - There were no patients with decreased TNF-α and IL-6 concentration. % 80 70 60 50 40 30 20 10 0 Increased TNF- No change TNF- Increased IL-6 No change IL-6 α Chart 1: Percentage of TNF-α and IL-6 levels in study group. We found that 33.6% of patients had increased in both TNF-α and IL-6 concentrations. The proportion of single increase of TNF-α concentration was 3.1 times higher than that in IL-6 concentration. 107
4. Journal of military pharmaco-medicine n o2-2018 2. Relation between TNF-α and IL-6 concentrations and some characteristics of patients. Table 3: Relation between TNF-α and IL-6 concentrations and hemodialysis duration (n = 107). Hemodialysis duration (year) TNF-α (ng/L) IL-6 (ng/L) < 1 (n = 6) 719.5 ± 216.4 8.7 ± 1.4 1 - < 5 (n = 37) 715.8 ± 219.3 9.2 ± 4.0 5 - < 10 (n = 52) 815.9 ± 335.8 13.3 ± 6.3 ≥ 10 (n = 12) 783.8 ± 185.8 14.8 ± 4.9 pANOVA 0.40 0.001 - Mean value of TNF-α concentration in study group were different in each hemodialysis duration groups. However, it was not significant difference with p > 0.05. - Mean value of IL-6 concentration increased with time of dialysis. There was a statistically significant association between IL-6 concentration and dialysis duration (p < 0.005). Table 4: Correlation between TNF-α and IL-6 concentrations and hemodialysis duration (n = 107). Hemodialysis duration Indexes Correlation equation r p TNF-α (ng/L) 0.15 0.13 IL-6 (ng/L) 0.46 < 0.001 y = 6.7 + 0.07x - IL-6 concentration had a proportional correlation with hemodialysis duration (r = 0.46; p < 0.001). - There was no correlation between TNF-α and hemodialysis duration (r = 0.15; p = 0.13). Table 5: Relation between TNF-α and IL-6 concentrations and hepatitis virus infection (n = 107). TNF-α (ng/L) IL-6 (ng/L) Status Elevated proportion Elevated proportion Mean ± SD Mean ± SD n (%) n (%) Without infection (n = 79) 744.7 ± 236.0 51 (64.6) 11.8 ± 6.0 35 (44.3) With infection (n = 28) 850.3 ± 373.0 19 (67.9) 11.9 ± 4.8 12 (42.9) p 0.008 0.75 0.90 0.90 - Mean value of TNF-α concentration in patients with hepatitis virus infection was significantly higher than that in whom without infection with p < 0.05. 108
5. Journal of military pharmaco-medicine n o2-2018 - There was no relation between IL-6 concentration and hepatitis virus infection status in study group (p > 0.05). Table 6: Relation between TNF-α and IL-6 concentration and preserved urine output status (n = 107). Status TNF-α (ng/L) IL-6 (ng/L) Preserved urine output (n = 81) 795.3 ± 292.6 12.9 ± 6.1 Non-preserved urine output (n = 26) 700.8 ± 228.7 8.5 ± 1.4 p 0.14 < 0.001 - TNF-α concentration was different between preserved urine output and non- preserved urine output patients, but this difference was not significant with p > 0.05. - IL-6 concentration was significantly higher in preserved urine output patients compared with non-preserved urine output patients (p < 0.001). Table 7: Relation between TNF-α and IL-6 concentrations and serum albumin concentration (n = 107). TNF-α (ng/L) IL-6 (ng/L) Elevated proportion Elevated proportion Characteristics Mean ± SD Mean ± SD n (%) n (%) Decreasing albumin < 35 802.6 ± 345.1 15 (62.5) 12.7 ± 6.2 15 (62.5) g/L (n = 24) Non-decreasing (n = 83) 763.5 ± 260.5 55 (66.3) 11.5 ± 5.5 32 (38.6) p 0.55 0.73 0.37 0.04 - Mean value of TNF-α and IL-6 concentration were higher in decreased albumin group compared with non-decreased group, but it was not significantly different with p > 0.05. - Elevated proportion of IL-6 concentration was significantly higher in decreased albumin group compared with non-decreased group (62.5% versus 38.6%) with p < 0.05. DISCUSSION patients, in whom inflammation is common. Chronic inflammation is high prevalent Certain pro-inflammatory cytokines, such in LHD patients, which is a strong as IL-6 and TNF-a, are considered as independent predictor of all causes and early drivers of the inflammatory response. CVD mortality in those population [4]. It When comparing the study group and may explain the excess CVD risk in LHD control group we found that TNF-α, and 109
6. Journal of military pharmaco-medicine n o2-2018 IL-6 levels in study group was significantly fully clearly understood yet, more and more higher than those in the control group evidences showed that cytokines obviously (p < 0.001). The percentage of patients play important roles in perpetuating the with increased TNF-α and IL-6 concentration chronic inflammatory state. TNF-α and were 65.4% and 43.9%, respectively. Our TNF-β were also important mediators in results also pointed out that 33.6% of the antiviral response. In addition, data patients had increased in both TNF-α and from related studies had been showed IL-6 concentration, 31.8% of patients had that the patients had contamination with increased of single TNF-α and this virus, and increased of T-cell response percentage in IL-6 was 10.3%. There (such as TNF-α production), which were no patients with decreased TNF-α correlated with the result of hepatitis virus and IL-6 concentration. Our results are in infection. There are significant differences good agreement with data publised in the ability to produce cytokines among previously: Babaei M [1], Cao H [2] and Jin K et al [5]. individuals [3]. In our study, mean value of IL-6 Residual kidney function (RKF), even concentration significantly increased at the low glomerular filtration rate (GFR) with hemodialysis duration (p < 0.005). levels in dialysis patients plays a crucial Apparently, dialysis time was associated role in clearance of uremic toxins, prevents volume overload and its sequelae, such with IL-6 rather than TNF-α. A number of as left ventricular hypertrophy (LVH) and studies in the world have suggested that congestive heart failure (CHF), and is the progression of fibrosis and atherosclerosis associated with improved metabolic increases with time of dialysis [7, 9]. If parameters. In our study, IL-6 concentration TNF-α is usually associated with acute was significantly higher in preserved inflammation (particularly secreted by urine output patients compared with macrophages, necrotic cells), IL-6 is non-preserved urine output patients associated with chronic inflammation and (p < 0.001). Research by Shafi T et al atherosclerosis. That is why IL-6 is related (2010) also showed a significant association to the dialysis time. between IL-6 and renal function in Our results also pointed out that mean hemodialysis patients [10]. Inflammation value of TNF-α concentration in patients is a common problem in hemodialysis with hepatitis virus infection was significantly patients, the increased of serum CRP and higher than those without infection with IL-6 levels directly affect the cardiovascular p < 0.05, while there was no relation events and survival of hemodialysis between IL-6 concentration and hepatitis patients. There had been reports about virus infection status in study group with the relation between residual kidney p > 0.05. Although the reasons leading to function and pre-inflammatory cytokine hepatitis virus infection have not been levels in dialysis patients [8]. 110
7. Journal of military pharmaco-medicine n o2-2018 Studying the relation between TNF-α (p < 0.005). IL-6 concentration had a and IL-6 concentration and serum albumin proportional correlation with hemodialysis concentration, we realized that percentage duration (r = 0.46; p < 0.001). of patients with elevated IL-6 level was - Mean value of TNF-α concentration in significantly higher in decreased albumin patients with hepatitis virus infection was group compared with non-decreased group significantly higher than those without (62.5% versus 38.6%) with p < 0.05. Kim infection with p < 0.05. There was no Y et al (2013) [6] also showed that IL-6 relation between IL-6 concentration and level was significantly correlated with serum hepatitis virus infection status in study albumin concentrations in hemodialysis group (p > 0.05). patients. Serum albumin levels decrease - IL-6 concentration was significantly with inflammation due to several causes, higher in preserved urine output patients including reduced synthesis, increased compare with non-preserved urine output catabolism, and translocation of albumin patients (p < 0.001). to extravascular pools. TNF-α and IL-1 - Elevated proportion of IL-6 concentration directly suppress appetite. Cytokines may was significantly higher in decreased also induce catabolism, leading to a albumin group compared with non- wasting illness that is indistinguishable decreased group (62.5% versus 38.6%) from prolonged starvation. with p < 0.05. CONCLUSIONS REFFERENCES * Serum TNF-α, and IL-6 concentration 1. Babaei M et al. Evaluation of plasma in study group: concentrations of homocysteine, IL-6, TNF- - TNF-α, and IL-6 level in study group alpha, hs-CRP, and total antioxidant capacity was significantly higher than those in the in patients with end-stage renal failure. Acta control group with p < 0.001. Med Iran. 2014, 52 (12), pp. 893-838. - The percentage of patients with 2. Cao H et al. Circulatory mitochondrial increased TNF-α and IL-6 concentration DNA is a pro-inflammatory agent in maintenance were 65.4% and 43.9%, respectively. hemodialysis patients. PLoS One. 2014, 9 (12), p. e113179. 33.6% of patients had an increase in both TNF-α and IL-6 concentration. 3. He J et al. The relationship between tumor necrosis factor-alpha polymorphisms * Relation between TNF-α and IL-6 and hepatitis C virus infection: a systematic concentration and some characteristics of review and meta-analysis. Ren Fail. 2011, 33 patients: (9), pp.915-922. - Mean value of IL-6 concentration 4. Hung A et al. Determinants of C-reactive increased with time of dialysis. There was protein in chronic hemodialysis patients: a statistically significant association between relevance of dialysis catheter utilization. IL-6 concentration and dialysis duration Hemodial Int. 2008, 12 (2), pp.236-243. 111
8. Journal of military pharmaco-medicine n o2-2018 5. Jin K, N.D.Vaziri. Elevated plasma 8. Pecoits-Filho R et al. Associations cyclophillin A in hemodialysis and peritoneal between circulating inflammatory markers and dialysis patients: a novel link to systemic residual renal function in CRF patients. Am J inflammation. Iran J Kidney Dis. 2017, 11 (1), Kidney Dis. 2003, 41 (6), pp.1212-1218. pp.44-49. 9. Pencak P et al. Calcification of coronary 6. Kim Y et al. Relative contributions of arteries and abdominal aorta in relation to traditional and novel risk factors of inflammation and inadequate protein intake to atherosclerosis in hemodialysis patients. BMC hypoalbuminemia in patients on maintenance Nephrol. 2013, 14, p.10. hemodialysis. Int Urol Nephrol. 2013, 45 (1), 10. Shafi T et al. Association of residual pp.215-227. urine output with mortality, quality of life, and 7. Lee C.T, et al. Biomarkers associated inflammation in incident hemodialysis patients: with vascular and valvular calcification in the choices for healthy outcomes in caring for chronic hemodialysis patients. Dis Markers. end-stage renal disease (CHOICE) study. Am 2013, 34 (4), pp.229-235. J Kidney Dis. 2010, 56 (2), pp.348-358. 112